Alpha-(alpha-carboxyacylamino) aralkyl-penicillins

ABSTRACT

OR A PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALT THEREOF WHEREIN R IS PHENYL OR THIENYL, R1 IS LOWER ALKYL, PHENYL, BENZYL, PHENOXY, BENZYLOXY, CARBOXYPHENYL OR CARBOXYBENZYL, R2 IS HYDROGEN OR LOWER ALKYL AND R3 IS HYDROGEN OR LOWER ALKYL, PHENYL OR BENZYL, AND A TYPICAL COMPOUND IS D-A-(BENZYLOXYCARBONYL)BPHENYLPROPIONAMIDO)-BENZYLPENICILLIN.   CO-NH-)PENAM   2-(HOOC-),3,3-DI(CH3-),6-(R3-OOC-C(-R1)(-R2)-CO-NH-CH(-R)-   A-(A-CARBOXYACYLAMINO)-ARALKYL PENICILLINS HAVING ACTIVITY AGAINST MICRO-ORGANISMS OF THE GENUS PSEUDOMONAS ARE DESCRIBED. THE PENICILLINS HAVE THE FORMULA:

Us. C 260-2391 United States Patent Office 3,647,780 Patented Mar. 7,1972 3,647,780 a-(a-CARBOXYACYLAMINO) ARALKYL- PENICILLINS Kenneth DavidHardy, Horsham, Sussex, England, asfigulor to Beecham Group Limited,Middlesex, Eug- No Drawing. Continuation of abandoned application Ser.No. 792,139, Jan. 17, 1969. This application Mar. 23, 1970, Ser. No.20,457

Claims priority, application Great Britain, Jan. 19, 1968,

Int. Cl. C0711 99/16 7 Claims ABSTRACT OF THE DISCLOSUREa-(u-Carboxyacylamino)-aralkyl penicillins having activity againstmicro-organisms of the genus Pseudomonas are described; The penicillinshave the formula:

or a pharmaceutically acceptable non-toxic salt thereof wherein R isphenyl or thienyl,

R is lower alkyl, phenyl, benzyl, phenoxy, benzyloxy,

carboxyphenyl or carboxybenzyl, R is hydrogen or lower alkyl and R ishydrogen, lower alkyl, phenyl or benzyl,

and a typical compound is D-u-[u(-benzyloxycarbony1)flphenylpropionamido] -benzylpenicillin,

This application is a streamlined continuation of Ser. No. 792,139,filed Jan. 17, 1969, now abandoned.

This invention relates to new penicillins.

In our US. Pat. No. 3,320,240 we have described and claimed newpenicillins of the general formula:

and non-toxic salts thereof, where R is an alkyl, aralkyl, aryl orheterocyclic group which may be substituted and X is a direct linkage ora divalent aliphatic, aromatic or heterocyclic radical which may besubstituted.

These compounds are of value as antibacterial agents, as nutritionalsupplements in animal food, as agents for the treatment of mastitis incattle and as therapeutic agents in poultry and animals, including man,in the treatment especially of infectious diseases caused byGram-positive and Gram-negative bacteria.

We have now found that certain compounds related to the general FormulaI above have particularly desirable properties especially in respect oftheir activity against certain micro-organisms of the genus Pseudomonas.

Accordingly, the present invention provides penicillins of the generalformula:

R1 s on,

I naooo-o-oonnonoo.Nn.oH oH o R. R on,

CON-OH.COOH

and non-toxic salts thereof, where R is a phenyl or thienyl group, R isan alkyl, aryl, aralkyl, aryloxy or heterocyclic group, R is a hydrogenatom or an alkyl group and R is a hydrogen atom or an alkyl, aryl oraralkyl group.

The salts are non-toxic salts including non-toxic metallic salts such assodium, potassium, calcium and aluminium, ammonia and substitutedammonium salts, e.g. salts of such non-toxic amines, as trialkylamines,including triethylamine, procaine, dibenzylamine,N-benzylbeta-phenethylamine, l-ephenamine, N,N-dibenzylethylenediamine,dehydroabietylamine, N,N-dehydroabietylethylenediamine and other amineswhich have been used to form salts with benzylpenicillin.

The penicillins of the present invention as hereinbefore defined otherthan those where R is a hydrogen atom, i.e. thew(a-alkoxycarbonylacylamino)aralkyl penicillins are preferably preparedby reacting an u-aminopenicillin of the general formula:

NHg

with a reactive derivative of the carboxylic acid R2 RI-b-C o o 11 whereR is a phenyl or thienyl group, R is an alkyl, aryl, aralkyl, aryloxy orheterocyclic group, R is a hydrogen atom or an alkyl group and R is analkyl, aryl or aralkyl group. The reactive derivative is preferably theacid chloride.

The a-aminopenicillin (III) may be employed in either epimericmodification or as the DL-mixture, but in general the D-epimers arefound to give the most active products.

The on (a carboxyacylamino)aralkylpenicillins (II; R =H) may be preparedby the catalytic hydrogenation of the corresponding benzyl esters (II; R=CH Ph). Alternatively, they may be prepared by mild alkaline hydrolysisof the corresponding aryl esters (II; R =ary1).

In general the a(a-carboxyacylarnino)aralkylpenicillins in which thea-carbon atom of the side chain has the D- configuration tend to be moreactive than those having the L-configuration.

The following examples illustrate the invention, the activity of thepenicillins being shown by the minimum inhibitory concentrations(M.IC.s) against two strains of Pseudomonas pyocyaneus, A and R59.

EXAMPLE 1 (a) Monobenzyl benzylmalonate Benzylmalonic acid (0.7 .g.,0.05 mol.) was mixed with dry ether (40 ml.) and treated with thionylchloride (5.95 g., 3.63 ml., 0.05 mol.) and dimethylformamide (1 drop).The mixture was refluxed for 3 hours on a hot water bath and the solventevaporated under reduced pressure. The residue was dissolved in freshdry ether (40 ml.), benzyl alcohol (5.4 g., 5.06 ml., 0.05 ml.) wasadded all at once, and the mixture refluxed for a further 2 hours. Thereaction was cooled to room temperature, washed with water (12.5 ml.)and extracted with saturated sodium bicarbo nate solution until theextracts were alkaline. The combined aqueous extracts were washed withether (50 m1.) and acidified with 5 N hydrochloric acid. Theprecipitated oil was extracted exhaustively with methylene chloride. Thecombined organic extracts were washed thoroughly with Water (6X 60 ml.),dried over anhydrous magnesium sulphate and evaporated. The oily residuecrystallised and was recrystallised from benzene/6080 petroleum ether togive a colourless crystalline solid 7 g. (41.3%) M.P.

3 62 to 64 C. Found: C, 71.12; H, 5.61. C H O requires C, 71.81; H,5.67.

(b) D-u [oc- (benzyloxycarbonyl fl-phenylpropionamido] benzylpenicillinsodium salt Monobenzyl benzylmalonate (2.84 g., 0.01 mol.) was mixedwith thionyl chloride (10 ml.) and heated in a water bath at 75 C. for 1hour. The excess thionyl chloride was evaporated under reduced pressure.The residue was dissolved in dry benzene (5 ml.) and again evaporated todryness to remove any residual thionyl chloride. The final residue wasdissolved in dry acetone (50 ml.) and added, with stirring, to asolution of D-a-aminobenzyl penicillin trihydrate (4.03 g., 0.01 mol.)in water (50 ml), N. sodium hydroxide ml.), N sodium bicarbonate ml.)and acetone ml.), cooled to 12 C. The reaction mixture was stirred atroom temperature for 2 hours. The resulting solution was extracted withether (3X ml.) and the extracts discarded. The aqueous layer was coveredwith ether (30 ml.) and acidified with N hydrochloric acid to pH 1.5.The ether layer was separated and the aqueous layer extracted withfurther ether (2X 30 ml.). The combined ether extracts were washed withwater (10 ml.) and extracted with N sodium bicarbonate solution to pH 7.The neutral aqueous extract was evaporated under reduced temperature andpressure. The residue was dried over phosphorus pentoxide in vacuo togive 5.8 .g. (91.1%) of the penicillin sodium salt as an amorphoussolid. M.I.C. ug/ml.) Pseudomonas pyocyaneus A.50; Pseudomonaspyocyaneus R.59.25.

(c) D-a-(a-carboxy-B-phenylpropionamido)benzylpenicillin disodium saltSodium D-a-[a-(benzyloxy-carbonyl)fi-phenylpropionamido]benzylpenicillin(3 g.) dissolved in Water (100 ml.) was added to a pre-hydrogenatedmixture of 5% palladium EXAMPLE 2 (a) D-ot- [a (benzyloxycarbonylphenylacetamido] benzylpenicillin sodium salt Monobenzyl phenylmalonate(5.4 g. 0.01 mol.) was converted to the acid chloride and reacted withD-ocaminobenzylpenicillin trihydrate (8.06 g. 0.02 mol.) as in Example1(b) to give 11 g. (88.3%) of the penicillin sodium salt. M.I.C.(,ug/ml.) Pseudomonas py'ocyaneus A.50; Pseudomonas pyocyan'eus R.59.50.

(b) D-a-(a-carboxyphenylacetamido)benzylpenicillin disodium salt D [0c(benzyloxycarbonyl)phenylacetamido]benzylpenicillin sodium salt wasreduced as described in Example 1(c) to give 2.1 g. (94.3%) of thepenicillin disodium salt as a colourless amorphous solid. M.I.C.(,ug/ml.) Pseudomonas pyocyaneus A.50; Pseudomonas pyocyaneus R.59.25.

EXAMPLE 3 (a) The following acids having the general Formula IV wereprepared as described in Example 1(a).

Analysis Found Calculated Yield, M.P.,

R R R percent 0. 0 H S O H S Ph Me CHzPh 70 .0 CH (OH2)3-- H CHzPh 65. 5a-thlenyl H CHzPh 38. 8 0 PhO II CHzPh 26. 6 1 PhCHz- H Ph 37 .8 Ph HOtH4CO2CH PlK0) 27. 4 .0 pCHEOCaHdCH H CHQPh 26.4 .1 pOlC5H CH2 H CHzPh65 .2 Ph H 0211:; 43. 5

H 011(01313): 62 3-thlenyl H CH(CH3)2 53 on calcium carbonate (9 g.) inwater ml.) and hydrogenated under positive pressure until no morehydrogen (b) The resultant acid chlorides of the above acids were usedto acylate D-a-aminobenzylpenicillin as dewas absorbed. The mixture Wasfiltered through Celite. scribed in Example 1(b) to give respectivelythe follow- The filtrate was shaken with ether (30 ml.) and acidifieding penicillins of the general Formula II:

M.I.C. (pg/ml.)

(0) Subsequently those penicillins having R =CH Ph were reduced asdescribed in Example 1(c) and the corresponding penicillins having R :Hwere isolated as the di-sodium salts as follows:

M.I.C. m1.)

Y m Pseudomtmas pyocyaneus R R1 R2 R3 periint A. Im

11 Ph Na 78.4 125 125 Na 75.2 125 12s Na 32.2 50 50 Na 62.7 125 50 Na36.2 125 250 EXAMPLE 4 15 or a pharmaceutically acceptable non-toxicsalt thereof wherein (a) L-a-[a(benzyloxycarbonyl)phenylacetamido]benzylpenicillin sodium salt R phenyl or thlenyl L aminobenzylpenicillinwas acylated with mono R1 is i g f benzyloxy car oxyp eny or car ox enzbenzyl phenylmalonyl chloride as described in Example R2 is hydrogen orlower ga 1(b) to give 2.95 g. (47.3%) of the penicillin sodium R3 ishydrogen, lower alkyl, phenyl or benzyl. Salt. (M PseudomfmasPyocyanells 2. The penicillin of claim 1 which is D-a-[a-(bCIIZylOXY-Pseudomonas pyocyaneus R-59-500-czltlrbonyl)fi-phenylpropionamido]-benzylpenicillin or a bcarboxyphenylacetamido)benZy1 p armaceutlcallyacceptable non-toxic saltthereof. (genicinin disodium Salt 3. Tlllle penicillin of clalm 1 whichis D-a(a-carboxy- B p enylpropionamido)benzylpenicillin or a phar- Thebenzyl ester Pemclnm (2 P 4(a) was maceutically acceptable non-toxicsalt thereof duceicllh as descrlbfifi 1n 2 351; 32R ti l"; 25 6 4. Thepenicillin of claim 1 which is I a-[a(benzylof e penlcl 111 18 A 125 Poxycarbonyl)phenylacetamido]benzylpenlcillin or a Pseudomonas Pyocyaneus2 omonas pharmaceutically acceptable non-toxic salt thereof. cyanells 5.The penicillin of claim 1 which is D-a-(a-carboxy- EXAMP 5phenylacetamido)benzylpenicillin or a pharmaceutically (a)a[u(Benzyloxycarbonyl)phenylacetamido]2- ep able non-tonic salt thereof.

thienylmethylpenicillin sodium salt 35 6. Tlljre p1e)n111l1m of claim 1which is D-a-[a-benzyloxycar ony p enoxyacetamido]benzylpenicillin or afroglAmrigaiiggignfiiggipeiglglmwiaipmgz i1:25 :22: pharmaceuticall yacceptable non-toxic salt thereof. (0 1 0)] was acylated with monobenzylphenyl- The pemcium of clalm is Ina-Enid zchloride as described inExample Kb) to give phenoxyacetamido)benzylpemcrllm or apharmaceutically 4 g of the penicillin sodium Salt. Mia 40 acceptablenon-toxic salt thereof. (pg/ml.) Pseudomonas pyocyaneus A.125; R.59.125.References Cited (b)a(a-Carboxyphenylacetamido)Z-thienylmethylpenicillin disodium saltUNITED STATES PATENTS The benzyl ester penicillin (2 g.) from 5(a) wasre- 3,320,240 967 Fosker et a1. 260-239;1 duced as described in Example1(c) to give 1.7 g. (94. 9%) of the penicillin di-sodium salt. M.I.C.ug/ml.) NICHOLAS RIZZO, Pflmafy EXamlIleI Pseudomonas pyocyaneus A.125;R.59.125.

What is claimed is: US. Cl. X.R. 1. A penicillin of the formula: 424.2711 s CH R 000 (I) QONHiIHCQNl-X-CH (2H CH CH R2 R CO N Cl'l-CCIOH

